Many different materials have been investigated to resist non-specific protein adsorption. Chemistries utilized for this purpose include, but are not limited to: polyethers (e.g., polyethylene glycol), polysaccharides such as dextran, hydrophilic polymers such as polyvinylpyrrolidone or hydroxyethyl-methacrylate, heparin, intramolecular zwitterions or mixed charge materials, and hydrogen bond accepting groups such as those described in U.S. Pat. No. 7,276,286. The ability of these materials in preventing protein adsorption varies greatly between the chemistries. Of these materials, only a few resist fouling to the degree required for short-term in vivo application. However, the few materials appropriate for short-term application, when used for longer periods of time in complex media or in vivo, exhibit significant fouling or other degradation, making them unsuitable for long-term applications. Furthermore, surfaces coated with materials that resist in vivo degradation are often susceptible to a noticeable decrease in fouling resistance over time.
WO 2007/02493 describes grafting sulfobetaine and carboxybetaine from self-assembled monolayers on gold substrates or from silyl groups on glass substrates using atom transfer radical polymerization (ATRP). Gold and glass are not appropriate substrates for many medical devices used in vivo. Self-assembled monolayers, such as thiol-based monolayers, may be unstable since the thiol group is not stably bound to the substrate.
U.S. Pat. No. 6,358,557 to Wang et al. describes the graft polymerization of substrate surfaces, but not with a high density of a highly non-fouling polymeric material. A thermal initiator is used to initiate polymerization, typically at temperatures greater than 85° C. Such temperatures are generally not suitable for many medical devices, such as thin-walled polyurethane catheters. Further, the “salt out” method described is generally not suitable for grafting polymers such as zwitterionic polymers.
Jian et al., Colloids and Surfaces B: Biointerfaces 28, 1-9 (2003) describes the surface modification of segmented poly(ether urethane) by grafting sulfobetaine zwitterionic monomer, but not with a high density of non-fouling material. The resulting materials are not sufficiently non-fouling to be useful in medical device applications.
Resistance of protein fouling in biocompatible solid surfaces can play an important role in a range of technological disciplines, including biotechnology, medicine, food processing, and pharmaceutical applications, to name a few. It is well known, for example, that protein adsorption and bacterial adhesion and colonization can result in infection and subsequent failure of implanted medical devices. Incidences of protein adsorption and fouling can be minimized by changing the physical and/or chemical properties of the biomaterial surface. This may include, for example, the employment of polymeric substrate surfaces that are resistant to biomaterials.
Although advances have been made in biomolecule-resistant polymer coatings generally, various flaws can be present in the surface structure of biocompatible materials, both globally and at particular locations and regions of the surface (whether a non-polymeric substrate surface, a polymeric substrate or polymer substrate coating). Such flaws may be the result of improper handling or artifacts of the manufacturing or polymerization process, or may be present on a substrate surface prior to polymer growth and/or deposition. Regardless of their source, such flaws can substantially limit the effectiveness of conventional polymer coatings and polymeric substrate surfaces. For instance, increased or decreased protein adsorption may result from changes in one or more of the specific chemical, morphological, and physical properties of the substrate or substrate coating. In general, the present invention is directed to processes for preparing articles having improved surfaces that will serve as substrates for non-fouling grafted polymer layers.